J.G.P. Pires

Cardiovascular risk factors, their associations and presence of metabolic syndrome in adolescents

OBJECTIVE To evaluate the occurrence of metabolic syndrome (MS) and independent associated risk factors in adolescents in the city of Vitória, Brazil. METHODS We assessed 380 adolescents aged 10 to 14 years attending public schools. Body mass index and blood pressure at rest were measured. Fasting plasma concentrations of total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and glucose were also obtained. RESULTS The prevalence of overweight was 9.6% for boys and 7.4% for girls, while obesity was found in 6.2 and 4.9%, respectively. Triglyceride concentrations were borderline or high in 6.8 and 3.4% of the boys and in 11.8 and 5.9% of the girls. HDL-cholesterol was below recommended levels in 8.5% of the boys and in 9.9% of the girls. Blood pressure at rest was borderline for 5.1% of the boys and 7.9% of the girls, while 3.4% of both boys and girls were hypertensive. Fasting glycemia was high in 0.6% of the boys and in 0.5% of the girls. In the group studied, 2.8% of the boys and 2.5% of the girls had two risk factors associated with MS. Prevalence of MS was 1.1% for boys and 1.5% for girls, and overall prevalence was 1.3%. CONCLUSIONS MS and associated cardiovascular risk factors are serious clinical conditions in this age group. A significant number of adolescents showed borderline results, which may increase the prevalence of MS or independent risk factors in the short term. More investments should be made in primary prevention, considering that early diagnosis is an issue of fundamental importance.

Effects of 5-HT3 receptor antagonists on neuroleptic-induced catalepsy in mice

Typical neuroleptics (e.g. haloperidol) can induce a cataleptic state in rodents by means of striatal DA receptor blockade. It has been shown that drugs which influence central serotonergic (5-HTergic) mechanisms can modify neuroleptic-induced catalepsy, suggesting that dopaminergic transmission is under 5-HTergic modulation. The aim of this study was to examine the effects of bemesetron and granisetron, two selective 5-HT3 receptor antagonists, on this catalepsy in mice. Catalepsy was induced with haloperidol (1.5 mg/kg, i.p.) and measured at 30-min intervals by means of a bar test. Drugs (or saline, for the controls) were injected i.p. 20 min before haloperidol, with each animal used only once. Bemesetron significantly reduced catalepsy at a dose of 1 mg/kg, whilst 10 mg/kg potentiated the phenomenon and 0.1 mg/kg was found to be without effect. Granisetron inhibited catalepsy at doses of 0.04 and 0.1 mg/kg while 4 mg/kg of the antagonist significantly increased the duration of catalepsy. These data suggest that 5-HT3 receptors play a role in neuroleptic-induced catalepsy. Considering the high affinities of both antagonists for 5-HT3 receptors, it is tempting to speculate that the potentiation of catalepsy by high doses of them is due to non 5-HT3 receptor mechanisms.

Acute effects of selective serotonin reuptake inhibitors on neuroleptic-induced catalepsy in mice

Depression found in Parkinson disease (PD) usually responds to selective serotonin reuptake inhibitors (SSRIs). Drugs that modify experimental neuroleptic catalepsy (NC) might affect extrapyramidal symptoms in PD. Therefore, the effects of SSRIs on NC were tested in mice, 26-36 g, separated by sex. Catalepsy was induced with haloperidol (H; 1 mg/kg, ip) and measured at 30-min intervals using a bar test. An SSRI (sertraline, ST; paroxetine, PX; fluoxetine) or vehicle (C) was injected ip 30 min before H. Dunnetts test was used for comparison of means. ST (1-5 mg/kg) or PX (1-5 mg/kg) attenuated NC, with a similar inhibition found in both sexes (5 mg/kg, 180 min: ST - males: 124 +/- 10 vs 714 +/- 15 s in C; females: 116 +/- 10 vs 718 +/- 6 s in C; PX - males: 106 +/- 10 vs 714 +/- 14 s in C; females: 102 +/- 10 vs 715 +/- 14 s in C). At 0.3 mg/kg, neither of these drugs affected NC. Fluoxetine (1-25 mg/kg) also inhibited catalepsy, although the effect was not dose-dependent; no differences were observed between males and females (5 mg/kg, 180 min: males, 185 +/- 14 vs 712 +/- 14 s in C; females, 169 +/- 10 vs 710 +/- 19 s in C). For these SSRIs, maximal inhibition of NC was obtained with 5 mg/kg, 180 min after H. These results are consistent with the hypothesis that serotonergic mechanisms modulate nigrostriatal transmission, and suggest that SSRIs are possibly safe in depressive PD patients.

Cardiovascular risk factors in a population of Brazilian schoolchildren

Epidemiological and clinical evidence suggests that a judicious diet, regular physical activity and blood pressure (BP) monitoring must start in early childhood to minimize the impact of modifiable cardiovascular risk factors. This study was designed to evaluate BP and metabolic parameters of schoolchildren from Vitória, Espírito Santo State, Brazil, and correlate them with cardiovascular risk factors. The study was conducted on 380 students aged 10-14 years (177 boys, 203 girls) enrolled in public schools. Baseline measurements included body mass index, BP and heart rate. The students were submitted to exercise spirometry on a treadmill. VO2max was obtained from exercise testing to voluntary exhaustion. Fasting serum total cholesterol (TC), LDL-C, HDL-C, triglycerides (TG), and glucose were measured. Nine point nine percent of the boys and 11.7% of the girls were hypertensive or had pre-hypertensive levels. There was no significant correlation between VO2max and TC, LDL-C, or TG in prepubertal children, but a slight negative correlation was detected in post-pubertal boys for HDL-C and TG. In addition, children with hypertension (3.4%) or pre-hypertensive levels (6.6%) also had comorbidity for overweight and blood lipid abnormalities (14% for triglycerides, 44.7% for TC, 25.9% for LDL-C, 52% for low HDL-C). The present study shows for the first time high correlations between prehypertensive blood pressure levels and the cardiovascular risk factors high TC, high LDL-C, low HDL-C in schoolchildren. These are important for the formulation of public health policies and strategies.

Evidence that 5-HT3 receptors in the nucleus tractus solitarius and other brainstem areas modulate the vagal bradycardia evoked by activation of the von Bezold–Jarisch reflex in the anesthetized rat

The effects of intracisternal (i.c.) application of the 5-HT3 receptor antagonist granisetron (0.016-0.16 microg kg-1) and the agonist phenylbiguanide (0.3-3 microg kg-1) on reflex bradycardia evoked by injection of phenylbiguanide (i.v.; 10 microg kg-1) were investigated in urethane anesthetized atenolol-pretreated rats. The effect of bilateral microinjection of granisetron (10 nmol per side, 100 nl) into the nucleus tractus solitarius (NTS) on the reflex was also investigated. Intracisternal administration of granisetron dose-dependently (0.016-0.16 microg kg-1) and significantly attenuated the reflex bradycardia whilst the highest dose given i.v. had no significant effect on the reflex bradycardia. Phenylbiguanide given i.c. only caused significant potentiation at the middle dose (1 microg kg-1), having no significant effects at the other doses. Neither granisetron nor phenylbiguanide given i.c. affected resting heart rate or blood pressure. Granisetron microinjected bilaterally into the NTS also significantly attenuated both reflex bradycardia and hypotension. It is concluded that excitation of cardiac vagal motoneurones evoked by cardiopulmonary afferents involves activation of 5-HT3 receptors located in the nucleus tractus solitarius and other brainstem areas.

Oral administration of L-arginine decreases blood pressure and increases renal excretion of sodium and water in renovascular hypertensive rats

The two-kidney, one-clip renovascular (2K1C) hypertension model is characterized by a reduction in renal flow on the clipped artery that activates the renin-angiotensin system. Endothelium dysfunction, including diminished nitric oxide production, is also believed to play a role in the pathophysiology of this model. Some studies have shown an effect of L-arginine (L-Arg, a nitric oxide precursor) on hypertension. In the present study we determined the ability of L-Arg (7 days of treatment) to reduce blood pressure and alter renal excretions of water, Na+ and K+ in a model of 2K1C-induced hypertension. Under ether anesthesia, male Wistar rats (150-170 g) had a silver clip (0.20 mm) placed around the left renal artery to produce the 2K1C renovascular hypertension model. In the experimental group, the drinking water was replaced with an L-Arg solution (10 mg/ml; average intake of 300 mg/day) from the 7th to the 14th day after surgery. Sham-operated rats were used as controls. At the end of the treatment period, mean blood pressure was measured in conscious animals. The animals were then killed and the kidneys were removed and weighed. There was a significant reduction of mean blood pressure in the L-Arg-treated group when compared to control (129 7 vs 168 6 mmHg, N = 8-10 per group; P<0.05). Concomitantly, a significant enhancement of water and Na+ excretion was observed in the 2K1C L-Arg-treated group when compared to control (water: 13.0 0.7 vs 9.2 0.5 ml/day, P<0.01; Na+: 1.1 0.05 vs 0.8 0.05 mEq/day, respectively, P<0.01). These results show that orally administered L-Arg acts on the kidney, possibly inducing changes in renal hemodynamics or tubular transport due to an increase in nitric oxide formation.

Gender-related differences in the effects of nitric oxide donors on neuroleptic-induced catalepsy in mice

It has been suggested that nigrostriatal dopaminergic transmission is modulated by nitric oxide (NO). Since there is evidence that gonadal hormones can affect extrapyramidal motor behavior in mammals, we investigated the effects of isosorbide dinitrate (ISD), linsidomine (SIN-1) and S-nitroso-N-acetylpenicillamine (SNAP), three pharmacologically different NO donors, on neuroleptic-induced catalepsy in 60- to 80-day-old male and female albino mice. Catalepsy was induced with haloperidol (1 mg/kg, ip) and measured at 30-min intervals by means of a bar test. Drugs (or appropriate vehicle) were injected ip 30 min before haloperidol, with each animal being used only once. ISD (5, 20 and 50 mg/kg) caused a dose-dependent inhibition of catalepsy in male mice (maximal effect 120 min after haloperidol: 64% inhibition). In the females only at the highest dose of ISD was an attenuation of catalepsy observed, which was mild and short lasting. SIN-1 (10 and 50 mg/kg) did not significantly affect catalepsy in female mice, while a significant attenuation was observed in males at the dose of 50 mg/kg (maximal inhibition: 60%). SNAP (20 mg/kg) significantly attenuated catalepsy in males 120 min after haloperidol (44% inhibition), but had no significant effect on females. These results basically agree with literature data showing that NO facilitates central dopaminergic transmission, although the mechanisms are not fully understood. They also reveal the existence of gender-related differences in this nitrergic modulation in mice, with females being less affected than males.

Evidence for the ability of central 5-HT1A receptors to modulate the vagal bradycardia induced by stimulating the upper airways of anesthetized rabbits with smoke

Cigarette smoke passed through the nasal cavity of atenolol pre-treated anesthetized spontaneously breathing rabbits caused a bradycardia which was significantly modified by intracisternal application of the 5-HT1A receptor ligands 8-OH-DPAT (50 micrograms.kg-1) and buspirone (200 micrograms.kg-1). 8-OH-DPAT attenuated while buspirone potentiated the bradycardia. These results support the view that 5-HT1A receptors play an important role in modulating the excitability of cardiac vagal motoneurones.

Activity of Angiotensin‐Converting Enzyme After Treatment with L‐Arginine in Renovascular Hypertension

The renin‐angiotensin system plays a role in the pathophysiology of renovascular hypertension. In addition, some studies have demonstrated a beneficial effect of L‐arginine (L‐Arg), the precursor of nitric oxide (NO), in this model of hypertension. This study was designed to investigate the effects of L‐Arg on cardiovascular parameters and on the activity of the angiotensin‐converting enzyme (ACE), after 14 days of renovascular hypertension. The experiments were performed on conscious male Wistar rats. Two‐kidney, one‐clip renovascular hypertension (2K1C) was initiated in rats by clipping the left renal artery during 14 days, while control rats were sham‐operated. One group was submitted to a similar procedure and treated with L‐Arg (10 mg/ml; average intake of 300mg/day) from the 7th to the 14th day after surgery, whereas the respective control group received water instead. At the end of the treatment period, the mean arterial pressure (MAP) was measured in conscious animals. The rats were sacrificed and the ACE activity was assayed in heart and kidneys, using Hip‐His‐Leu as substrate. In a separate group, the heart was removed, the left ventricle (LV) was weighed and the LV/body weight ratios (LV/BW) were determined. We observed significant differences in MAP between the L‐Arg‐treated and untreated groups (129 ± 7 vs. 168 ± 6 mmHg; P < 0.01). The cardiac hypertrophy described for this model of hypertension was attenuated in the 2K1C‐L‐Arg‐treated group (14th day, wet LV/BW: 2K1C‐L‐Arg = 1.88 ± 0.1; 2K1C = 2.20 ± 0.1 mg/g; P < 0.05). L‐Arg administration caused an important decrease in cardiac ACE activity (2K1C‐L‐Arg: 118 ± 15; 2K1C: 266 ± 34 µmol/min/mg; P < 0.01). L‐Arg also decreased the ACE activity in the clipped kidney by 47% (P < 0.01), but not in the nonclipped kidney. These data suggest that increased NO formation and reduced angiotensin II formation are involved in the anthihypertensive effect of orally administered L‐arginine.

High-frequency transcutaneous electrical nerve stimulation reduces pain and cardio-respiratory parameters in an animal model of acute pain: Participation of peripheral serotonin

The objective of this study was to investigate the effect of high-frequency transcutaneous electrical nerve stimulation (HF-TENS) in antihyperalgesia, assessed through changes of sciatic nerve activity and its effects on cardiorespiratory parameters, using formalin-induced nociception in anesthetized rats. The animals were divided into formalin (FORM) and HF-TENS groups. All rats received injections of 5% formalin (50 μl, right hind-paw). The sciatic nerve activity and cardiopulmonary parameters (mean arterial pressure, heart rate, and respiratory frequency) were measured, and then the serum levels of serotonin (5-HT) were determined by an enzyme-linked immunosorbent assay kit. The formalin injection was able to increase the sciatic nerve activity, heart rate, and respiratory frequency. The treatment with HF-TENS significantly reduced the sciatic nerve activity and respiratory frequency 20 minutes after formalin injection and was able to increase serum 5-HT. Furthermore, when comparing the groups, reductions in the mean arterial pressure, heart rate, respiratory frequency, and sciatic nerve activity were shown at different times. Thus, we concluded that HF-TENS was capable of inducing analgesia, which was most likely related to increased serotonin release. Moreover, we demonstrated that TENS was able to block the adverse cardiovascular and respiratory changes induced by pain. Further neurophysiological studies are necessary to clarify the intrinsic mechanisms underlying HF-TENS-induced analgesia.